WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Introduction

Neoplasia is driven by deregulated intracellular signalling. Mutations and overexpression in human tumours and cell lines implicate the small GTPase RAC and its activators, the guanine nucleotide exchange factors (GEFs), in the formation and dissemination of a range of cancers. Furthermore, the effects of ablating genes encoding RAC proteins or RAC GEFs in mouse or of pharmacologically inhibiting RAC-GEF/RAC interactions strongly suggest that targeting RAC signalling could constitute an effective cancer treatment. Owing to multiple physiological roles of RAC and moreover RAC functions that antagonise tumour dissemination, sustained suppression of RAC signalling could however be detrimental.

Given this challenge, the research of the Cell Signalling group aims to distinguish RAC-dependent effects that promote tumour growth and progression from those that antagonise tumour progression so that RAC signalling might ultimately be targeted more effectively. Previously we have found that the RAC GEF TIAM1 is essential for RAS-induced tumourigenesis due to its requirement for cell survival and proliferation. Moreover, we have shown that activation of RAC can promote cell migration and invasion connected to post-translational modifications and its activation by specific GEFs. However, alternative pathways, again regulated by post-translational modifications that we have identified, utilise RAC to strengthen cell-cell adhesion and antagonise migration and invasion. We are currently investigating novel roles of the RAC pathway in controlling migration and invasion and in lung tumourigenesis in vivo.

Selected Publications

Porter AP, White GRM, Mack NA, Malliri A. (2019)
The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia.
Journal of Cell Science 132(14) jcs230086. PubMed abstract

Woroniuk A, Porter A, White G, Newman DT, Diamantopoulou Z, Waring T, Rooney C, Strathdee D, Marston DJ, Hahn KM, Sansom OJ, Zech T, Malliri A. (2018)
STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap.
Nature Communications 9(1):2124. PubMed abstract

Diamantopoulou Z, White G, Fadlullah MZH, Dreger M, Pickering K, Maltas J, Ashton G, MacLeod R, Baillie GS, Kouskoff V, Lacaud G, Murray GI, Sansom OJ, Hurlstone AFL, Malliri A. (2017)
TIAM1 antagonizes TAZ/YAP both in the destruction complex in the cytoplasm and in the nucleus to inhibit invasion of intestinal epithelial cells.
Cancer Cell, 31(5):621-634.e6. PubMed abstract

Marei H, Carpy A, Woroniuk A, Vennin C, White G, Timpson P, Macek B and Malliri A. (2016) Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration.
Nature Communications (7):10664-79. PubMed abstract

Whalley HJ, Porter A, White GRM, Diamantopoulou Z, Castañeda-Saucedo E and Malliri A. (2015) Cdk1 phosphorylation of the Rac activator Tiam1 is required for centrosomal Pak activation and regulation of spindle assembly in mitosis.
Nature Communications (6):7437-51. PubMed abstract

Vaughan L, Tan C, Chapman A, Nonaka D, Mack NA, Smith D, Booton R, Hurlstone AF and Malliri A. (2015)
HUWE1 ubiquitylates and degrades the RAC Activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion.
Cell Reports (10):88-102. PubMed abstract

Castillo-Lluva S, Tan CT, Daugaard M, Sorensen PH and Malliri A. (2013)
The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation.
Oncogene (32):1735-42. PubMed abstract

Mack NA, Porter AP, Whalley HJ, Schwarz JP, Jones RC, Khaja AS, Bjartell A, Anderson KI and Malliri A. (2012)
β2-syntrophin and Par-3 promote an apicobasal Rac activity gradient at cell-cell junctions by differentially regulating Tiam1 activity.
Nature Cell Biology (14):1169-80. PubMed abstract

Castillo-Lluva S, Tatham MH, Jones RC, Jaffray EG, Edmondson RD, Hay RT and Malliri A. (2010)
SUMOylation of the GTPase Rac1 is required for optimal cell migration.
Nature Cell Biology (12):1078-85. PubMed abstract

Rooney C, White G, Nazgiewicz A, Woodcock SA, Anderson KI, Ballestrem C and Malliri A. (2010)
The Rac activator STEF (Tiam2) regulates cell migration by microtubule-mediated focal adhesion disassembly.
EMBO Reports (11):292-98. PubMed abstract

Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F and Collard JG. (2002)
Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours.
Nature (417):867-71. PubMed abstract